The Canadian National Breast Screening Study conducted in the 1980s and led by researchers at the University of Toronto evaluated the efficacy of breast cancer screening in reducing mortality from breast cancer. Because the research was supposedly a “gold standard” randomized controlled trial, its results, published in academic journals and reported in the media, have influenced public perceptions and informed policy on mammography screening in several countries.
However, over the past decades, flaws in this study have come to light. My colleagues and I learned of failures in randomization, and we and other researchers have found other serious problems. We think these flaws strongly suggest the publications of CNBSS results should be retracted. Despite being informed of the flaws in this study in 2021, the University of Toronto has not adequately or appropriately addressed these issues.
The CNBSS was configured as two separate randomized clinical trials, one for women in their 40s at entry and the other for women in their 50s. In CNBSS1, 50,000 women ages 40-49 were supposedly randomly assigned to the intervention arm, in which they would receive up to five annual screens with two view film mammography plus clinical breast examination by a nurse, or to the control arm, where they received a single clinical examination at entry and usual care (essentially, no screening) afterwards. In CNBSS2 for 40,000 women, the randomization was between the intervention of mammography plus a clinical breast exam versus clinical exam only.
When the results of CNBSS1 and CNBSS2 were first published in 1992, the investigators reported no difference in mortality from breast cancer between the arms in either trial. This finding contrasted with positive results in several other studies. In fact, the investigators initially, and falsely, claimed screening was leading to excess deaths from breast cancer in the younger women. That claim was eventually retracted. As well, results from CNBSS were later used by one of its principal investigators to produce unrealistically high estimates of overdiagnosis attributed to mammography screening.
I and other colleagues have criticized the CNBSS over the years for, among other serious problems, strong indications of bias in randomization. These concerns led to a forensic review in 1995 of the randomization of the trial, but, for reasons not entirely clear, the mandate of the review did not include interviewing the staff crucial to the randomization process. The review proved inconclusive and left the key question of subversion of randomization open.
In 2021, my colleagues and I became aware of eyewitness evidence staff members had steered some participants with symptoms of breast cancer into the mammography arm of the study. At all but one trial site, all women received a clinical breast examination before getting their study arm allocation. The staff registering the women into the study were aware of the exam results. Entering a woman with significant findings to the intervention arm would assure her of an immediate mammogram.
According to eyewitness testimony, well-meaning staff members could, and did, steer such individuals into the screening arm with the intention of providing a symptomatic woman with an immediate mammogram, without appreciating the consequences for randomization this entailed. As we have explained, moving even a few women from their intended random allocation in the control arm to the intervention arm after discovery of palpable abnormalities could shift the trial findings from demonstrating a mortality benefit from screening to suggesting a mortality detriment.
In light of this new evidence, later in 2021 we contacted the Canadian Cancer Society (CCS), whose subsidiary, The National Cancer Institute of Canada, had sponsored the CNBSS. The CCS then approached the University of Toronto, via the Dean of Medicine, informing them of this evidence and requesting a review. In the meantime, we published an article describing the evidence for subversion of randomization.
After several months with no response from the university, we followed with a letter to the university’s Research Ethics Board. Eventually we were informed that the matter had been referred to the Office of Research Integrity, which is the responsibility of the Vice President of Research and Innovation of the University of Toronto. Finally, in December of 2021 we were told that our concerns would be investigated and an external three-member panel would be appointed to do this. This was not consistent with the university’s established framework for investigations of research ethical issues.
After another long gap, we learned on June 14, 2022, the panel members had been selected by Lorraine Ferris, the associate vice president of research and innovation at the University of Toronto. Two of the members of this committee, Mette Kalager and Peter Jüni, had previously been on record supporting the results of the CNBSS and in one case, had co-published on issues around screening with one of the trial’s principal investigators. If CNBSS were to be invalidated, both of these individuals would have to reverse pointed statements they had made publicly. We were surprised the university would appoint either of these individuals to the committee, given their clear conflicts of interest (for the same reason, that these panel members did not immediately recuse themselves also was surprising).
We immediately raised these concerns to Prof. Ferris. In her response, she stated the investigation would go forward with this panel. She said it was challenging to find suitably qualified panel members for such a review. We explained our concerns regarding subversion of a randomized control trial do not require people with specific expertise in breast cancer screening studies to resolve them; it is largely a matter of consideration of proper conduct of any such study.
In a follow-up letter, we indicated we would continue to protest the process the university had chosen to investigate our concerns and to push for a more appropriately constituted panel. At the same time, we agreed to be interviewed by whatever review panel was appointed by the university. We did not want, by refusing to cooperate, to provide an excuse for the university to back away from its responsibility to conduct an investigation. On Aug. 2, 2022, we received a response from Prof. Ferris that she was unwilling to reconsider the composition of the panel.
The panel did interviews by Zoom in the Fall of 2022, including one with me. But the witness list was not made available to those of us who had raised the initial concerns, nor have the statements made by the various witnesses been shared.
In 2023, we were informed by Professor Ferris that she expected the review to be completed by March of 2024. However, that date passed without event. We requested a meeting with the current Provost, Trevor Young, and that was arranged for March 28 of last year. Professors Ferris and Leah Cohen, vice president of research and innovation, and strategic initiatives, were also scheduled to attend. The meeting was abruptly cancelled by the Provost on the afternoon of March 26. We have heard nothing since.
This is not the first time the University of Toronto has delayed or failed in fulfilling its responsibilities to safeguard the ethical conduct of medical research. Notably, in the late 1990s, Nancy Olivieri, a hematologist clinician researcher conducting a study with an industrial collaborator to evaluate a new drug for treating thalassemia, observed adverse effects on patients. When she attempted to discontinue the study and voice her concerns, she was faced with intense harassment by the pharmaceutical manufacturer and by some of her academic colleagues. Her request for intervention from the university –- which was in the midst of negotiating a $20 million building donation from the manufacturer — did not receive an adequate response. Ultimately the matter had to go to an external review, which vindicated her.
At this point, almost four years have elapsed since we brought our concerns to the attention of the University of Toronto and, as far as we can see, nothing has happened. Perhaps the long delay in the review suggests that, in light of overwhelming evidence, the university is no longer able to credibly support the conduct or the results of the CNBSS. Or perhaps it means that by delaying its review, the university hopes the problem will go away.
The CNBSS has influenced policy and opinions of primary healthcare providers and women, discouraged opportunities for earlier detection of cancer, and, in turn, resulted in delays in cancer detection. The publications of results from CNBSS must be retracted.
Martin J. Yaffe is a medical physicist and imaging scientist at Sunnybrook Research Institute and Professor of Medical Biophysics at The University of Toronto. His research over the past 45 years has focused on the earlier detection, diagnosis and characterization of cancer.
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It looks strange that this text, describing the work done mostly after 2020, does not mention the Gotzsche’s 2013 systematic review – the first review separated the ‘suboptimal’ trials. In this influential review, the Canadian trial was classified as having adequate randomization.
Furthermore, here the report PMCID: PMC1226907 is mentioned as “and other researchers have found other serious problems.’ If we look at it, we find that ” The authors’ thorough review of ways in which the randomization could have been subverted failed to uncover credible evidence of it.”
Such omissions and mispresentation weaken the argument for retraction of the Canadian study
Unfortunately, the Gotzsche review, mentioned by Dr. Vlassov, has been largely discredited and Dr. Gotzsche has been removed from the Cochrane Group. He claimed that of the randomized, controlled trials, only the Malmo and Canadian trials had adequate random assignment while, inappropriately, dismissing all the other trials. In fact, multiple reviews, the scientific facts, and the testimony of those who participated in the Canadian studies confirmed that the Canadian trials violated the fundamental rules for randomized, controlled trials and their results are unreliable.
Random allocation is fundamental and critical in these trials. The goal of Randomized Controlled Trials is to produce 2 identical groups of women such that each woman in the study arm will have a “twin” in the control arm. If nothing else was done, there should be the same number of women diagnosed with breast cancer in both groups and the same number of deaths from breast cancer in both groups over time.
It is critical that nothing can be known about the participants before they are randomly assigned to the study or control arms of the trial that might compromise random allocation.
It has been clearly documented that most of the women who participated in the Canadian trials underwent a clinical breast examination prior to allocation. Not only were women who were found to have a clinical abnormality on these examinations allowed to participate in these trials of mammography screening, but the results of the clinical examination were provided to the coordinators prior to allocation (another major violation).
Compounding the error is the fact that, once again in violation of the fundamental rules for RCT, assignment was not blinded. The coordinators could assign women to either arm of the trial since assignment was on open lists which identified the assignment. If they wanted to assign a woman to the screening arm to be certain that she would get a mammogram, they could, literally, skip a line and then fill in the skipped space with the next participant, and the nonrandom allocation would be undetectable. The data clearly show this happened with statistically significantly more women with advanced cancers being assigned to the screening arm than the control arm in CNBSS1.
The Principal Investigator has never allowed the coordinators to be interviewed to determine how often this happened, but the data have strongly suggested it, and it has been documented that women referred to surgeons with clinically evident breast cancers were then referred to these trials of screening. There is now “eyewitness” testimony that some of these women were assigned to the “screening arm” out of random order. All of these concerns have been verified, and the major imbalances in the published data have confirmed that these trials were corrupted by nonrandom assignment.
This does not even include the well documented failure and poor quality of the mammography used in the Canadian Trials.
It is unethical for the Toronto review to be taking so long and allowing these compromised trials to be used to deny women access to screening and the benefits of early detection.
Daniel B. Kopans, M.D.
Professor of Radiology, Harvard Medical School
For me, there is a promotion of the unbalanced point by the primary author as well as Dr. Kopans.
Discrediting esteemed experts like Peter Juni and Peter Gotzsche is no an appropriate option. Years ago, when PCG first introduced in the practice of systematic review, the separate analysis of good and not-so-good trials, it was rejected by the community, but then became the standard practice. In the mammography sys review, separate analysis does not support the mammography screening, and the analysis of the totality of data only marginally supports. This attack on the Canadian study has obvious purpose: exclusion of “these compromised trials to be used to deny women access to screening and the benefits of early detection.”
Women are not denied access to screening because of the quality of the 30-years old data. Major problem is the absence of good modern data, relevant to modern treatment options.
Vasiliy Vlassov may be misinterpreting my comments. Regarding Prof. Juni, I am in no way impugning his credibility as a scientist. My point was that because of the strong statements that he has made against mammography screening and his support of the findings of the CNBSS trials, he should not have been considered by the University of Toronto to be in an appropriate position to render an objective review of concerns regarding ethical and methodological improprieties in these trials. He and Prof Kalager both have a professional conflict of interest in this matter.
I also note that in a 2000 publication with Ole Olsen in The Lancet, Prof. Gotzsche did mention the concerns that had been raised regarding subversion of randomization in CNBSS, however, he dismissed them, accepting the findings of an inquiry, which as Prof Kopans has stated, had major gaps. When he endorsed the CNBSS as a well-conducted trial he could not have been aware of the eyewitness evidence of interference with the randomization which formally came to light in 2021 and was described in my post.
– Martin Yaffe
The medical profession needs to stop making decisions that harm the people they purportedly serve, to benefit or protect colleagues or funding dollars. First do no harm…stop paying lip service to your oath.